Arthritogenic alphaviruses—an overview

Arthritogenic alphaviruses—an overview420 | JULY 2012 | VOLUME 8 www.nature.com/nrrheum
Immunovirology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia (A. Suhrbier). Groupe de recherche immunopathologie et maladies infectieuses (GRI, EA4517), Université de la Réunion et CHR Félix Guyon, Plateau technique du CYROI, 2 rue Maxime Rivière, 97470 Sainte-Clotilde, La Réunion, France (M.C. JaffarBandjee). Laboratoire d’Hémato- microbiologie, Hôpital Félix Guyon CHR de la Réunion, 97 405 Saint- Denis, La Réunion, France (P. Gasque).
Correspondence to: A. Suhrbier [email protected]
Arthritogenic alphaviruses—an overview Andreas Suhrbier, Marie-Christine Jaffar-Bandjee and Philippe Gasque
Abstract | Mosquito-transmitted alphaviruses causing human rheumatic disease are globally distributed and include chikungunya virus, Ross River virus, Barmah Forest virus, Sindbis virus, o’nyong-nyong virus and Mayaro virus. These viruses cause endemic disease and, occasionally, large epidemics; for instance, the 2004–2011 chikungunya epidemic resulted in 1.4–6.5 million cases, with imported cases reported in nearly 40 countries. The disease is usually self-limiting and characterized by acute and chronic symmetrical peripheral polyarthralgia–polyarthritis, with acute disease usually including fever, myalgia and/or rash. Arthropathy can be debilitating, usually lasts weeks to months and can be protracted; although adequate attention to differential diagnoses is recommended. The latest chikungunya virus epidemic was also associated with some severe disease manifestations and mortality, primarily in elderly patients with comorbidities and the young. Chronic alphaviral rheumatic disease probably arises from inflammatory responses stimulated by the virus persisting in joint tissues, despite robust antiviral immune responses. Serodiagnosis by ELISA is the standard; although international standardization is often lacking. Treatment usually involves simple analgesics and/or NSAIDs, which can provide relief, but better drug treatments are clearly needed. However, the small market size and/or the unpredictable and rapid nature of epidemics present major hurdles for development and deployment of new alphavirus-specific interventions.
Suhrbier, A. et al. Nat. Rev. Rheumatol. 8, 420–429 (2012); published online 8 May 2012; doi:10.1038/nrrheum.2012.64
Introduction Alphaviruses are a genus of enveloped, positive sense, single-stranded RNA viruses, which are usually trans- mitted by mosquitoes, and together with the genus Rubivirus belong to the Togaviridae family. Alphaviruses are commonly referred to as ‘Old World’ and ‘New World’ viruses, with Old World viruses (Table 1, Figure 1) gen- erally associated with rheumatic disease in humans and ‘New World’ viruses (which include Venezuelan, Eastern and Western Equine Encephalitis viruses) primarily associated with potentially fatal encephalitic disease in the Americas. The arthritogenic alphaviruses comprise chikungunya virus (CHIKV), Ross River virus (RRV), Barmah Forest virus (BFV), o’nyong-nyong virus (also known as Igbo Ora), the Sindbis group of viruses and Mayaro virus1,2 (Table 1, Figure 1). Symptomatic infection of adults with these alphaviruses is nearly always associ- ated with rheumatic disease, primarily poly arthralgia and/or polyarthritis, which can be chronic and debilitat- ing. The global distribution of these viruses, increased international travel, economic develop ment, changes in mosquito vectors and the potentially explosive nature of epidemics can all contribute to these diseases being seen more frequently by doctors and rheuma tologists globally. In this Review, we describe the epidemiology, patho genesis, disease, diagnosis and interventions for arthritogenic alpha viruses, with particular focus on information pe rtinent to health-care professionals.
Alphavirus epidemiology Chikungunya virus CHIKV was first isolated in 1952 in Tanganyika (pre- sent day Tanzania); however, the first description of the disease might have been by David Bylon in 1779 during an epidemic in Jakarta.3 Regular epidemics have occurred since then, primarily in Africa and Asia, with early out- breaks (including one in the USA and Caribbean) poten- tially confused with epidemic dengue fever.3,4 The largest epidemic of CHIKV disease ever recorded took place in 2004–2011 and was associated with the emergence of a clade of viruses that were efficiently transmitted by Aedes albopictus,5–7 a mosquito vector that has seen a dramatic global expansion in its geographic distribu- tion in the past 30 years.8 The epidemic began in Kenya, spread across the Indian Ocean Islands to India (where an estimated 1.4–6.5 million cases have occurred6) and South East Asia, reaching Myanmar (formerly known as Burma) in 2010.7 A number of cases were reported in New Caledonia in the Pacific Ocean in 2011.9 The attack rate for CHIKV disease can be very high; a survey on Grande Comore Island in 2005 suggested an attack rate of ~50%10 and, in Reunion Island (French Indian Ocean territory), 266,000 cases of CHIKV disease were reported (38% of the population) during 2005–2006. The first auto chthonous (endogenously transmitted) infections in Europe occurred in Italy in 2007 (>200 cases)5,6 and in France in 2010.11 Due to international travel, imported CHIKV cases have now been reported in nearly 40 countries including USA, Japan and several European countries.6,9,12–14
Competing interests The authors declare no competing interests.
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CHIKV is a biosafety level 3 pathogen in most coun- tries and is listed as a US National Institute of Allergy and Infectious Diseases category C priority pathogen.15 The US Army recognizes CHIKV as a potential bio- logical weapon, and CHIKV is considered a possible agent for bioterrorism owing to the potential for in fection via aerosol.16
Ross River virus and Barmah Forest virus RRV was first isolated in 1959 from mosquitoes trapped beside the Ross River in Queensland, Australia. BFV was first isolated in 1974 from mosquitoes collected in the Barmah Forest, Victoria, Australia. The viruses are endemic and enzootic in Australia (with RRV also found in Papua New Guinea; Figure 1), with most cases occurring in northern Australia during the wet season —usually December to February—when mosquito popula tions are at their peak.17 RRV and BFV infection are notifiable to public health authorities in Australia.17–19 Australian-based analyses suggest changing land prac- tices and climate change are likely to increase the range and activity of these and other mosquito-borne in fectious diseases in the future.17,20
The Sindbis virus group Sindbis virus was first isolated from mosquitoes in 1952 in Egypt and is the most widely distributed arbo virus found in Eurasia, Africa and Oceania.2,21,22 How ever, Sindbis viral diseases in humans are largely restricted to Northern Europe (Table 1, Figure 1), where this organism is endemic, with intermittent outbreaks typi- cally seen in late summer or early autumn.2,21,22 Cases are also occasionally reported in Australia, China and South Africa.2,21,22
O’nyongnyong virus O’nyong-nyong virus first emerged as disease- causing entity in Uganda in 19592 and so far has caused at least three outbreaks in Africa, one of which involved >2 million cases (Table 1, Figure 1). Although o’nyong- nyong virus is more closely related to CHIKV than the other arthritogenic alpha viruses, it is a genetically dis tinct virus.23 As with CHIKV, the attack rate for o’nyong-nyong virus can be very high (45–68%).2
Mayaro virus Mayaro virus was first isolated in 1954 and is enzootic in northern South America. The virus causes sporadic human cases and recurrent small outbreaks, usually associ ated with residence in, or travel to, humid tropical forests.2,24,25
Mosquito transmission Arthritogenic alphaviruses (Table 1) are maintained in the wild by continuous cycles of transmission between mosquitoes and vertebrate hosts: primates for CHIKV,26 primarily macropods (kangaroos and wallabies) for RRV and BFV,16,17 forest birds for Sindbis virus,2 unknown for o’nyong-nyong virus, and possibly various mammals for Mayaro virus.27 These reservoirs, on various occasions,
Key points
Alphaviruses that cause rheumatic disease are globally distributed and cause endemic disease in various locations and, occasionally, large unpredictable epidemics
The 2004–2011 outbreak of chikungunya virus was the largest ever recorded, involving 1.4–6.5 million cases, with imported cases reported in nearly 40 countries
Alphaviral disease is characterized by fever, rash, and/or myalgia, and generally symmetrical and peripheral, often debilitating, polyarthralgia and/or polyarthritis, which usually lasts weeks to months
The arthropathy is rarely destructive and is usually treated with simple analgesics and/or NSAIDs, although relief of symptoms is often inadequate, with better treatments needed
The pathogenesis of chronic arthralgia and/or arthritis probably arises from inflammatory immune responses induced by the virus persisting in joint macrophages, despite robust antiviral immune responses
Adequate attention to differential diagnoses in patients with long-term chronic disease is recommended as other rheumatic conditions might be responsible for symptoms
can lead to human infections via mosquito bite, with large epidemics usually associated with subsequent urban transmission cycles (human–mosquito–human).18 For instance, for CHIKV in Africa, the sylvatic cycle (primate–mosquito–primate) involves various forest dwelling Aedes species that occasionally seed human infections, with subsequent urban transmission cycles involving A. albopictus and/or A. aegypti vectors that cause human outbreaks.26 Whether a sylvatic cycle provides a reservoir of CHIKV in Asia is less clear,26 although CHIKV isolates have been recovered from long-tailed macaques in Malaysia.28
Pathogenesis Infection with alphaviruses results in a brief, usually 5–7 days long, viraemia,6,29,30 which is controlled pri- marily by IFN-α/β and antibodies.1,31–34 A wide range of cell types and tissues have been shown to be infected by arthritogenic alphaviruses, including monocytes and/or macrophages,1,29,35–37 dendritic cells,29,38 syno vial and dermal fibroblasts,29,31,35,39 endothelial cells,29,31,35,39 muscle cells,35,40,41 periosteum,42 and perhaps keratino- cytes.43 Widespread infection of these cells and the
Table 1 | Alphaviruses associated with rheumatic disease
Virus Occurrence
Chikungunya virus Large sporadic epidemics
Ross River virus Mean of ≈4,000 cases per annum in Australia17
An epidemic occurred in 1979–1980 >60,000 cases in some of the Pacific Islands18
Barmah Forest virus Mean of ≈1,000 cases per annum in Australia18
O’nyong-nyong virus Rare epidemics, >2 million cases in 1959–196130,104
Mayaro virus Occasional small outbreaks (30–100 cases)24,122
Sindbis virus2,21,22
Ockelbo virus Mean ≈30 cases per annum (Sweden)
Pogosta virus Mean ≈140 (range 1–1,282) cases per annum (Finland)
For geographical distribution of these disease outbreaks see Figure 1.
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associated inflammatory immune responses6 probably account for the acute symptoms caused by these viruses —pr imarily fever, polyarthralgia– polyarthritis, rash and myalgia (Table 2).
The central feature of adult disease caused by arthrito- genic alphaviruses is the often debilitating poly arthralgia and/or polyarthritis that lasts from weeks to months (Table 2).2,5,6,26,44,45 No strong evidence exists that auto- immune responses (that might be induced by viral infec- tions) are important for, or substantially contribute to, viral arthropathies. For multiple arthritogenic viruses, evidence indicates that arthropathies are due to inflam- matory responses induced by viruses and/or their prod- ucts residing and/or replicating within joint tissues.46 Consistent with this view, CHIKV has been shown to persist in various tissues for up to 44 days post-infection in monkeys, with CHIKV antigen and RNA detected in macrophages for 90 days and 55 days after infection, respectively.29 In one patient with CHIKV infection, CHIKV RNA and protein was found in synovial macro- phages 18 months after infection.47 In addition, RRV RNA has been detected in synovial tissue from those infected with RRV 5 weeks after the onset of symptoms.1 How these ordinarily cytopathic (ap optosis-inducing) viruses can persist for extended periods in the face of robust neutralizing antibody, T-cell and IFN-α/β responses29,48 remains unclear. The virus might evade neutraliza tion by antibodies by hiding in apoptotic blebs
and maintain infection in macrophages through contin- uous rounds of infection, apoptosis and phagocyto sis, with the phagocyte being infected via the phagosome.1,39 Evasion of T-cell responses might occur via the rapid shutdown of host-cell protein synthesis (a charac teristic of alpha viral infections of mammalian cells38), which could limit the number of cell surface major histo- compatibility molecules that can present viral antigens to T cells.49 Some evidence suggests that alphaviral RNA might be reverse transcribed by endo genous reverse transcriptases and integrate into host DNA.50
Cells infected with alphaviruses have also been shown to be less responsive to IFN-α/β,38 with nonstructural viral proteins able to inhibit IFNα/β receptor signalling.51 Engagement of Fc receptors by alphavirus– antibody complexes might also suppress antiviral responses in macrophages.52,53 The inflammatory infiltrate in the synovial fluid of patients with RRV disease is pri marily monocytic, with macrophages showing an inflam- matory phenotype and large phagocytic inclusions.1 Elevated levels of CC-chemokine ligand 2 (CCL2, also known as MCP-1), TNF and IFN-γ were found in the synovial fluids from such patients.54 The synovial fluid of a patient with chronic CHIKV disease at 18 months showed monocytes and macrophages with large inclu- sions, natural killer (NK) cells and CD4+ T cells, with polymorphonuclear cells largely absent, and elevated levels of CCL2, IL-6 and IL-8.47 Monkey and mouse
RRV and BFV* RRV outbreak 1979–1980 Sindbis virus‡
O’nyong-nyong virus§
Mayaro virus
CHIKV epidemics
1963–1965 1973 1982–1985 1991–1995 2001–2003 2004–2011
1779 1823–1825 1827–1828 1871–1872 1901–1902 1951–1953
Figure 1 | Approximate geographical locations of diseases associated with arthritogenic alphaviruses. For CHIKV disease, locations of documented large outbreaks are shown;3,4,7,9,26,112 epidemics prior to 1902 are shown in dashed lines and were initially classified as outbreaks of dengue, but were likely to have been due to CHIKV.3 *Geographical locations of RRV and BFV diseases overlap, with BFV restricted to the Australian mainland.17,74 ‡Main location of diseases caused by the Sindbis virus family.22 §O’nyong-nyong virus disease outbreaks in 1959–1961 (East Africa), 1996–1997 (Uganda) and 2003 (West Africa).30,104 Mayaro virus disease outbreak regions.17,25,74 Abbreviations: BFV, Barmah Forest virus; CHIKV, chikungunya virus; RRV, Ross River virus.
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CHIKV disease models also show pronounced mono- nuclear infiltrates, primarily monocytes, macro phages and NK cells.29,33
Analysis of serum cytokines and chemokines asso- ciated with CHIKV infection in humans has not pro- duced a coherent picture.47,48,55–58 Taken together with animal studies,29,33 serum IL-6, IFN-α/β, IFN-γ and CCL2 were upregulated in most studies. Granulocyte colony- stimulating factor, granulocyte monocyte colony- stimulating factor, IL-7, IL-12, IL-13, IL-17, and CXC-ligand 10 (CXCL10, also known as IP-10) were upregulated in human studies;47,48,55–58 whilst TNF was upregulated in some human47,48,55–58 and animal studies.29,33 CCL2, TNF, IFN-γ, IL-6 and IL-1β have been found to be induced by a number of arthritogenic viruses, with these inflammatory mediators also prominent in rheumatoid arthritis.46 Mouse models of RRV disease have also implicated macrophage migration inhibitory factor59 and complement60 as important factors in the development of alphaviral rheumatic disease.
A large body of literature exists detailing the molecular aspects of host–virus interactions for alphavirus infec- tions. As this literature is outside the clinical focus of this article, we refer readers to some excellent reviews in the area.6,38,61 Many of these studies have used Sindbis virus, which in mice behaves like an encephalitic virus rather than an arthritogenic virus.
Clinical features Acute phase The main symptoms of disease caused by arthritogenic alphaviruses are summarised in Table 2. The normal time course, based on CHIKV disease, is summarized in Figure 2. For CHIKV infection, viral loads usually range from 1 × 105 to 1 × 109 viral RNA copies per ml of blood,62 with the viraemia usually lasting 5–7 days (Figure 2).5,13 CHIKV disease is characterized by an abrupt onset of fever coincident with the viraemia, reaching 39–40 °C in some cases, and resulting in chills and rigors.63–65 Fever can be treated with anti pyretic agents,63 although such treatment might not be particularly effective (although the exact reasons why are unknown).66 Aspirin is best avoided for CHIKV disease owing to the risk of bleed- ing.63,66 Polyarthralgia and/or polyarthritis usually begins around the time of fever onset and is usually symmetri- cal. Peripheral joints (interphalangeal joints, wrists and ankles) and large joints (such as shoulders, knees and spine) are often affected.64,65,67 Joint effusions can be seen in most cases63,67—joint symptoms can fluctuate, but do not usually change anatomical location. In our experience, treatment usually involves NSAIDs and/ or simple analgesics. Skin manifestation can appear 2–4 days after onset of fever, usually a maculopapular rash (often pruritic), although a series of other skin con- ditions have been reported.63,68–70 The rash usually occurs
Table 2 | Symptoms of disease in adults caused by arthritogenic alphaviruses
Virus Usual incubation period (range)
% Asymptomatic Frequency of main symptoms (%)
Other symptoms noted (% frequency)
CHIKV 2–6 days (2–12)
≈5–18 Fever: 90 Rash: 40–50 Myalgia: 90 Arthralgia or arthritis: >95
Fatigue, tenosynovitis, headache, nausea, oedema, vomiting, conjunctivitis, occasional bleeding gums and epistaxis*
Toivanen (2008)2
RRV 7–9 days (3–21)
55–75 Fever: 20–60 Rash: 40–60 Myalgia: 40–80 Arthralgia or arthritis: 80–100 (3–6 months)
Fatigue (>50), headache, photophobia, lymphadenopathy, sore throat and rarely encephalitis*
Harley & Suhrbier (2012)17
Harley et al. (2001)19
Mylonas et al. (2002)44
Flexman et al. (1998)74
BFV 7–9 days Unknown Fever: 50 Rash: 40–60 Myalgia:50–80 Arthralgia or arthritis: 70–95
Lethargy (90) and headache 60 Flexman et al. (1998)74
Passmore et al. (2002)124
Sindbis virus
2–10 days Very common* Fever: 15–40 Rash: 90 Myalgia: 50 Arthralgia or arthritis: 95
Fatigue (60), headache (40) nausea (13) and dizziness (16)
Brummer-Korvenkontio et al. (2002)21
Laine et al. (2004)22
Kurkela et al. (2005)45
O’nyong- nyong virus
Unknown Unknown Fever: 80–100 Rash: 70–90 Myalgia: 70 Arthralgia or arthritis: 60–100
Headache (83), pruritis (71), lymphadenopathy (45%), red eyes (45) and bleeding gums (3)
Kiwanuka et al. (1999)30
Posey et al. (2005)104
Mayaro virus
Unknown 8 Fever:100 Rash: 30–50 Myalgia: 75 Arthralgia or arthritis: 50–90
Headache (60–100), oedema (58), retroocular pain (40–60), dizziness (25), anorexia (22), nausea (18), sore throat (18), swollen lymph nodes (17%), vomiting (4–14), diarrhoea (9), bleeding gums (4.5)
Azevedo et al. (2009)24 Tesh et al. (1999)125
Percentages for key symptoms have been rounded up; generally percentages should be viewed as approximate as cohort numbers were often small. The rash associated with arthritogenic alphavirus infection is usually maculopapular and often itchy. No major differences between sexes have been reported. *Percentages not researched. Abbreviations: BFV, Barmah Forest virus; CHIKV, chikungunya virus; RRV, Ross River virus
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on the trunk and limbs and only rarely on the face.63,68–70 This rash has been reported to occur in as few as 20%70 and >80% of cases,71 but usually occurs in 40–50% of patients.72,73 A series of additional symptoms have also been noted, including fatigue and headache (Table 2). Haematological findings include leukopaenia with lympho cyte predominance, occasionally thrombocyto- penia, and elevated erythrocyte sedimentation rate and C-reactive protein levels.55,63
The disease course for other alphaviral arthritides represent variations on the theme described above for CHIKV (Table 2). For RRV, the rash has been reported to occur before, after, or at the same time as arthropathy (with purpura occasionally found).18,19,44,74 Polyarthralgia and/or polyarthritis can be severe, with joint effusions often present, although usually small in size. Raised erythrocyte sedimentation rates can occur, but decrease within a few weeks. Serum C-reactive protein levels are rarely increased.18,19,44,74 BFV disease cannot reliably be distinguished from RRV disease by symptoms alone, although the rash is more common and florid (vesicu- lar in ~10% of cases), with arthritic symptoms also less pronounced.74 For Sindbis virus, joint swelling is seen in ~50% of patients.22,45 No haemorrhagic manifestations have been reported for RRV, BFV or Sindbis virus dis- eases, and aspirin is sometimes used for treatment.44,74 Mayaro virus and o’nyong-nyong virus infections largely follow similar patterns (to each other and to CHIKV), and resemble CHIKV disease by showing occasional haemor rhagic manifestations (Table 2).
Differential diagnoses for acute symptomatic infec- tions with arthritogenic alphaviruses, include other infectious arthritides (for example, dengue fever, parvo- virus B19, infectious mononucleosis, Lyme disease, measles, varicella, measles, rubella, human herpesvirus 6, hepatitis B, HIV46), autoimmune arthritides (for example, rheumatoid arthritis, systemic lupus erythematosus),
Still’s disease, malaria, yellow fever, meningitis, rheu- matic fever, leptospirosis and drug reactions.19,24,45,63,70,74,75 Persistent, distinct mono articular arthritis is not consist- ent with alphaviral disease. Comor bidities (see below) and co-infections might also need to be considered in the diagnosis.76,77
Chronic phase The defining feature of most alphaviral arthritides is chronic, episodic, often debilitating, polyarthralgia and/ or polyarthritis, which is often associated with fatigue (Table 2). Although most patients progressively recover within several weeks, in some the disease can last for months.44,45,55,66,78 NSAIDs and/or simple analgesics can provide relief, but this therapeutic approach is often inadequate.4,10,44,74 The period of chronic joint pain seems to be somewhat reduced for BFV infection compared with RRV.74
Protracted disease—primarily arthralgia—is well documented for Sindbis virus,45 RRV44 and CHIKV dis ease.78–84 For instance, CHIKV arthritic disease is reported to remain unresolved after 6 months to 3 years in 1.6–57% of…